N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated gamma-secretase |
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Authors: | Narlawar Rajeshwar Pérez Revuelta Blanca I Baumann Karlheinz Schubenel Robert Haass Christian Steiner Harald Schmidt Boris |
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Affiliation: | 1. Clemens Schöpf-Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstr. 22, D-64287 Darmstadt, Germany;2. Laboratory for Alzheimer’s and Parkinson’s Disease Research, Ludwig Maximilian University München, Schillerstr. 44, D-80336 München, Germany;3. F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Preclinical Research CNS, Bldg. 70/345, CH-4070 Basel, Switzerland |
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Abstract: | N-Sulfonylated and N-alkylated carbazolyloxyacetic acids were investigated for the inhibition and modulation of the Alzheimer's disease associated gamma-secretase. The introduction of a lipophilic substituent, which may vary from arylsulfone to alkyl, turned 2-carbazolyloxyacetic acids into potent gamma-secretase modulators. This resulted in the selective reduction of Abeta(42) and an increase of the less aggregatory Abeta(38) fragment by several compounds (e.g., 7d and 8c). Introduction of an electron donating group at position 6 and 8 of N-substituted carbazolyloxyacetic acids either decreased the activity or inversed modulation. The most active compounds displayed activity on amyloid precursor protein (APP) overexpressing cell lines in the low micromolar range and little or no effect on the gamma-secretase cleavage at the epsilon-site. |
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